Abstract
The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.
| Original language | English |
|---|---|
| Pages (from-to) | 5006-5009 |
| Number of pages | 4 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 27 |
| Issue number | 22 |
| DOIs | |
| Publication status | Published - 2017 Nov 15 |
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Keywords
- High-throughput screening
- Keap1
- Metabolic stability
- Nrf2
- Protein-protein interaction inhibitor
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry
Cite this
Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor. / Yasuda, Daisuke; Yuasa, Akihiro; Obata, Rika; Nakajima, Mao; Takahashi, Kyoko; Ohe, Tomoyuki; Ichimura, Yoshinobu; Komatsu, Masaaki; Yamamoto, Masayuki; Imamura, Riyo; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo; Mashino, Tadahiko.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 22, 15.11.2017, p. 5006-5009.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor
AU - Yasuda, Daisuke
AU - Yuasa, Akihiro
AU - Obata, Rika
AU - Nakajima, Mao
AU - Takahashi, Kyoko
AU - Ohe, Tomoyuki
AU - Ichimura, Yoshinobu
AU - Komatsu, Masaaki
AU - Yamamoto, Masayuki
AU - Imamura, Riyo
AU - Kojima, Hirotatsu
AU - Okabe, Takayoshi
AU - Nagano, Tetsuo
AU - Mashino, Tadahiko
PY - 2017/11/15
Y1 - 2017/11/15
N2 - The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.
AB - The Keap1-Nrf2 system is an attractive target for drug discovery regarding various unmet medical needs. Only covalent inhibitors for protein-protein interaction (PPI) between Keap1 and Nrf2 to activate Nrf2 have been approved or are under clinical trials, but such electrophilic compounds lack selectivity. Therefore, specific non-covalent Keap1-Nrf2 PPI inhibitors are expected to be safer Nrf2 activators. We found a novel class of non-covalent Keap1-Nrf2 PPI inhibitor that has a benzo[g]indole skeleton and an indole-3-hydroxamic acid moiety and that exhibits significant PPI inhibitory activity. Additionally, the benzo[g]indole-3-carbohydrazide derivatives were newly prepared. The benzo[g]indole derivatives showed a stronger Keap1-Nrf2 PPI inhibitory activity than Cpd16, a previously reported non-covalent PPI inhibitor. Moreover, most of the PPI inhibitors showed a high metabolic stability in a human microsome system with a low cytotoxicity against HepG2 cell lines, which suggests that novel benzo[g]indole-type Keap1-Nrf2 PPI inhibitors are expected to be biological tools or lead compounds for Nrf2 activators.
KW - High-throughput screening
KW - Keap1
KW - Metabolic stability
KW - Nrf2
KW - Protein-protein interaction inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85031426399&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85031426399&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2017.10.008
DO - 10.1016/j.bmcl.2017.10.008
M3 - Article
VL - 27
SP - 5006
EP - 5009
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 22
ER -